US3892771A - Substituted dihydroisoindoles - Google Patents

Abstract

Substituted dihydroisoindoles e.g., 1-( Alpha -hydroxy-pchlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole are prepared from corresponding 1-(substituted phenacyl)-1(substituted phenyl)-3-ethoxy-1H-isoindole, and are useful in the treatment of lipidemia.

Description

United States Patent Eberle July 1, 1975 SUBSTITUTED DIHYDROISOINDOLES [52] US. Cl. 260/326.1; 260/325; 424/274 M ,N [51] Int- Cl. C07d 27/00; C07d 27/48 [75] Invent K hem J 58 Field of Search 260/325, 326.1; 424/274 [73] Assignee: Sandoz, lnc., Hanover, NJ.

. Primar ExaminerElbert L. Roberts 22 F] d: l 9, 1973 y 1 I e Ju y Attorney, Agent, or Firm-Gerald D. Sharkin; Robert PP N04 377,642 S. Honor; Thomas O. McGovern Related US. Application Data [63] Continuation-impart of Ser. No. 323,629, Jan. 15, [57] ABSTRACT 1973, abandoned, which is a continuation-in-part of Ser. No. 301,660, Oct. 27, 1972, abandoned, which is a continuation-in-part of Ser. No. 240,277, March 31, 1972, abandoned, which is a continuation-in-part of Ser. No. 220,494, Jan. 24, 1972, abandoned, which is a continuation-in-part of Ser. No. 170,332, Aug. 9, 1971, abandoned.

Substituted dihydroisoindoles e.g., l-(a-hydroxy-pchlorophenethyl l -(p-chlorophenyl )-2,3- dihydroisoindole are prepared from corresponding 1- (substituted phenacyl)-l-(substituted phenyl)-3- ethoxy-ll-l-isoindole, and are useful in the treatment of lipidemia.

35 Claims, No Drawings 1 2 SUBSTITUTED DIHYDROISOINDOLES mers. Racemic and diastereoisomeric mixtures of the compound of formula (I) may be separated into indi- This application is a continuation-in-part of copendid i s b v ntional techniques, ing U.S. Patent application Ser. No. 323,629, filed Jan. The compounds of the formula I are obtainable by 15, 1973, now abandoned. which in turn is a continuathe following reaction scheme:

R R2 R3 }2 R3 3 2 CH X CH (1H IN M! 03 Z \A (LI) R (I) tioninpart of copending U.S. Patent application Ser. wherein No. 301,66O,f1led Oct. 27, 1972 now abandoned which R,, R R R and the proviso are as previously dein turn in a continuation-in-part ofU.S. Patent applicafined; and tion Ser. No. 240,277, filed Mar. 31, l972 now aban- X is -CHOH or CO-; doned which in turn is a continuation-in-part of U.S. Z is CO or Patent application Serv No. 220,494, filed Jan. 24, i 1972 now abandoned, which in turn is a continuationin-part of U.S. Patent application Ser. No. 170,332, filed Aug. 9, 1971. now abandoned. B

This invention relates to substituted dihydroisoindoles and to their preparation. In particular, the appliand cation relates to l-(a-hydroxy-substituted phenethyl)- A is hy rog n'when Z is CO- or V l-(substituted phenyl)-2,3-dihydroisoindoles, their AB together represent a second carbon to nitrogen pharmaceutically acceptable acid addition salts, inter ond when Z is mediates used in their preparation and to their use as hypocholesterolemic agents.

The compounds of this invention may be represented 2 5' by the following formula: B

reducing a compound of the formula (II) with diborane R2 R (I) in a suitable inert organic solvent. Although the partic- 3 40 ular solvent used is not critical, hydrogen solvents, e.g.,

benzene, toluene, xylene and the ethers such as die- CH H thylether, tetrahydrofuran and dioxane are preferred,

M i h especially tetrahydrofuran. The production of compounds (I) may be carried out at a temperature of from about 0 to 80C, preferably 20 to 30C. The reaction time may vary widely and is usually in the range of from 1 to 48 hours. The reaction can be carried out in an inert atmosphere such as helium, argon, or nitrogen. Recovery of the compounds of formula (I) may be af- 50 fected using conventional techniques, e.g., filtration,

where R and R each independently represent hydrogen or halo having an atomic weight of 19 to 36 and R and R each independently represents hydrogen; lower alkyl having 1 to 4 carbon atoms, e.g., TZLILZZZSQZZ' iiilirlfl lilii if??? if recrystalhzamni p p y The compounds of the formula (II) in which X is and the like; halo having an atomic weight of 19 to CO- and Z IS 36 or trifluoromethyl;

provided that when both R and R are trifluoromethyl "y H they are not on adjacent carbon atoms, or pharmaceu- 25 tically acceptable acid addition salts thereof.

The compounds of formu a P0 IWO symme is the preferred starting material and may be prepared ric carbon atoms and therefore exist as four optical isoby the following procedure:

Vii H M N N (III) f (IIIa.) OC l-i The compounds of the formula (I) are prepared by Continued GH -C Y-CH fi (Iv) q Rh where metal reducing agent preferably an alkali metal boro- MH is an alkali metal hydride hydride reducing agent in an inert solvent. The particu- Y is halo having an atomic Weight of 35 80 and lar alkali metal reducing agent used is not critical al R4 and the provlso are as Previously though sodium borohydride is the preferred reducing finedagent. The particular solvent used will depend on the The Compounds of formula (Ha) are Prepared by 20 reducing agent used and include lower alkanols, hydrotreating a compound offormula (Ill) first with an alkali carbons, Such as benzene, toluene and Xylene, and mflal hydride and then with a Substituted phenzlcylha' ethers, such as diethyl ether, tetrahydrofuran and dioxlide in a suitable inert organic solvent. The alkali metal ane with the borohydrides and with the alkali metal hyfiride is preferably sPdlum hydride or Potasslum drides, all of the foregoing excluding the alkanols. The dride. The particular inert solvent used is not critical process is Suitable effected ata temperature of from but dimethylformamide is particularly preferred. The 7 o to 80C preferably o to for the more temperature is not critical, but the process is preferably five alkali metal hydrides and to for the alkali came? out a temoperature of i about 0 80 metal borohydrides. The reaction time is not critical fispeciany 20 to 30 The can gamed out and may for example vary from 1 to 5 hours. The reacm an inert atmosphere such as previously indicated and 30 tion is preferably Carried out in an inert atmosphere the time may vary widely and is usually in the range of such as nitrogen argon or heliurm l to 24 hours. Recovery f the produc y The process for preparing the compounds of formula fected usmg conventional techmques filtratlon (llb) yields two racemic isomers, both of which contain recrystallization two enantiomers. The racemic isomers are readily sep- The Compounds of formula (H) m Yvhlch arated from each other by conventional techniques, CHOH- may be prepared by the following reaction chromatotraphy scheme: The compounds of formula (II) in which Z is -CO R and A is hydrogen can be prepared in accordance with l 40 the following scheme:

CH2C R3 0 R o h A H+ (IIc) R. where [MH] is an alkali metal reducing agent and A, Z, R R R R and the proviso are as previously 5 defined. where The compounds of formula (llb) are prepared by X, R R R R d h proviso are as defined treating a compound of formula with an alkali above.

The compounds of formula (lld) are prepared by hydrolyzing a compound of the formula (lle) in an inert solvent under acidic conditions. i.e., at a pH value of less than 3 and preferably from 1 to 2. Although the 6 ylene chloride, conveniently at a temperature of from about to C for about 2-16 hours.

The pharmaceutically active isomers of the compounds of formula (I) in resolved form may conveparticular acid used to provide the acidic conditions is 5 niently be prepared by the following reaction scheme:

by treatment with triethyloxonium tetrafluoroborate in a solvent such as chlorinated hydrocarbons, e.g.. meth- Separation where h R2! R3! R41 above,

The asterisks indicate that the isomer is present in essentially chiral form, i.e., in about percent by weight or greater optically pure form.

The reduction of the compound of formula (Ilf) is carried out in the same manner as the reduction of compound above and leads to a mixture of two isomers, the nature of which will depend on the initial isomer'of the compound (IIf) The resulting isomeric mixture (Hg) is separated into individual isomers (lIg') in the second stage of the process, employing conventional techniques, e.g. column chromatography.

In the final stage ofthe process, the separated isomer of formula (llg) is reduced with diborane in an inert organic solvent in the same manner as the reduction of the compounds of formula (ll) above is carried out.

The resulting products may be isolated and purified using conventional techniques. The above process is particularly useful in preparing the compounds of formula (I) in which R is in the para position.

The compounds of formula (Hf) may be produced in accordance with the following reaction scheme:

and the proviso are as defined i R1: Rh

052cc rz'leael uI'aItS Catalyst (vI) (VII) where The present invention also encompasses the levo and dextro acid halides of formula (VI) which are prepared Y halo havmg an atomlc Welght of about to 80 15 by halogenating the respective levo or dextro acid and . (VIII) with an morganlc acid hallde, e.g., SOCI PCl R4 and the Prom" are as Set above" or SOBr- The reaction is illustrated in the following The compounds of formula (IIf) are prepared by scheme using a thionyl halide, the preferred halogenattreating the corresponding isomer of formula (VI) with ing agent.

(VIII) (VI) :1 Compound of formula (VII) in a solvent and in the where presence ofa Friedel Crafts catalyst. The particular sol- 3g Y, R and R are as set out above. vent used in the reaction is not critical; but halogenated The reaction is carried out in excess halogenating alkanes such as methylene dichloride, ethylene dichloagent or inert solvent. The preferred inert solvents are ride and the like, alkane such as hexane or heptane, benzene, toluene, pentane, hexane, heptane, methylethers such as diethyl ether, tetrahydrofuran and the ene dichloride, chloroform and the like, especially eth' like are preferred, and excess reactant of formula (VII) 40 ylene dichloride. Although the time and temperature of is especially preferred. The Friedel Crafts catalyst used the reaction are not Critical, it is preferred that the recan be any of the conventional Friedel Crafts catalysts, action be run for approximately 30 minutes to 24 hours for example, ferric chloride, stannic chloride, boron triat a temperature between about 30C. and 125C, and fluoride, zinc chloride and especially aluminum trichloespecially at the reflux temperature of the system. It is ride. Although the temperature of the reaction iS not also preferred that an N,N-di lower alkyl aliphatic acid critical, it is preferred that the reaction be run at temamide, such as dimethyl acetamide or dimethylformperatures between about -70 to 100C, preferably be amide be added to the reaction mixture to facilitate the tween to 30C and more especially between 50 reaction. One of the above inert atmospheres may also to 0. The reaction can be carried out an inert atmobe used. The acid halide may be recovere'd by conven sphere such as already indicated and the reaction 50 tional techniques, e.g., evaporation or distillation. should be run for from about 30 minutes to 20 hours. The racemic formtof compound (VI) can be pre- The product is separated by conventional techniques, pared by the above procedure using compound (Vllla) Chromatography I below, the racemic form of compound (VIII).

It will be appreciated that compound (He) in which The Compounds of formula (VIII) are novel and are Z is CO- and A is hydrogen can be prepared by the included within the scope of this invention, and may be above process by using the racemic form of compound prepared in accordance with the following reaction (VI). scheme:

B01; Resolution [H20] II (VIIIa) (VIIIb) he e of the compounds (IX) may be effected using conven- BOH is an optically active base and tional techniques eg. evaporation, extraction, etc. R and R are as defined above. The hydrolysis of the ester (IX) to the acid (Villa) The compounds of formula (VIII) are prepared by is carried out using an acid or base hydrolyzing agent resolution and decomposing of the diastereoisomeric 5 i n eous solvent. The acidic hydrolyzing agents salts IIIb) formed y treilting t e omp n of O are the same as those used above in the decomposition mula (Villa) with an optically active base in an inert of compound (VIIIb) and the basic hydrolyzing agent solvent. The optically active base can be any of the can be any of the standard basic hydrolyzing agents standard basic resolving agents, such as cinchonine cinpreferably potassium hydroxide or sodium hydroxide. Chonidine, quinine. rychnine. morphin d t e like, The aqueous solvent can be water or water plus a water especi lly brucinethe Solvent used can be inert miscible organic solvent such as the lower alcohols havsolvent. preferably lower alkanols such as methanol, i l to 4 c rbon atoms especially methanol, ethanol ethanol. etc. acetone, tetrahydrofuran and the like. esand the like. Although the temperature is not critical, pecially methanol. Although the temperature of the re it is preferred that the reaction be carried out at a temaction is not critical it is preferred that the reaction be perature of from 20 to l50, especially between 50 to carried out at from about to 150C. preferably 80. The acid (VIIla) is recovered by conventional to 30C. The time ofthe reaction is not critical and can techniques, for example, evaporation or precipitation. range from few minutes to several hours. The diastere- Many of the compounds of formulas (IV), (V) and oisomers (VIIIb) are resolved by conventional tech- (VII) are known and are readily prepared according to niques, e.g., fractional crystallization. methods disclosed in the literature. Compounds of for- I The decomposition of compound (VIIIb) to the optimulas (IV), (V) and (VII) which are not specifically cally active acid (VIII) is carried out by treating the isodi lo ed may be prepared by methods analogous to lated diflstefeoiwmer 0f fQfmula with an acid those in the literature from known starting materials.

in an inert aqueous solvent. The particular acid used is The compounds offormula (I) and (la) are useful benot Criti al and in rga acids Such as hydrochloric cause they possess pharmacological activity in animals. acid. sulfuric acid and the like or organic acids such as I i l compounds (I) d (l are usef l as trifluroacetic acid can be used. The preferred acids are h li id i agents i th treatment f li id i i the inorganic acids, especially hydrochloric acid. The particular, hyperlipoproteinemia, as indicated by the particular sol ent used and the temperature and time fall in cholesterol levels in male albino Wistar rats condition for the reaction are not critical and are the i hi 110 to 130 g, i i i ll Th rats are i same as in the preparation of the diastereoisomers salts r i d on drug-free laboratory h di f Seven d above. The pro III) i recovered y nand then devided into groups of8 to 10 animals. Each tional techniques, e.g., precipitation and recrystalligroup, ith th ex e ti of the t l, i then i e zation. orally 30 milligrams per kilogram of body weight per The compounds of formula (Villa) ar pr p r y diem of the compound for six days. At the end of this the following reaction scheme: period, the animals are anesthetized with sodium hexo- ME Hydrolysis (VIIIa) 5 YCH COOR a 2 I ca coorg N (III) (IX) om where barbital and bled from the carotid arteries. Serum or MH is an alkali metal hydride plasma samples are collected and 1.0 ml. of serum is 5 is lower alkyl having 1 t0 4 Carbon atoms and added to 9.0 ml, redistilled isopropanol. Two autoana- 1 and 2 are 85 Sat 011t lyzer cupsful of a mixture of zeolite-copper hydroxide The compounds o rm are p p y and Lloydds reagent (Kersler, E., and Lederer, H. treating a compound of o u II) with an alkali I965, Technicon Symposium, Madiad Inc., New York, metal hydride followed by a halo-acetic acid ester in an 345-347) are added, and the mixture is shaken for l inert solvent and hydrolyzing the ester (IX) obtained. hour. Cholesterol levels are determined using this sam- The haloacetic acid ester can be either bromoacetic ple by the standard Technicon N 24A (cholesterol) acid ester or chloroacetic acid ester, but the former is m h d l Th mean serum h l l levels are preferred. The alkali metal hydride is preferably sothen computed and the hypocholesterolemic activity is dium hydride or potassium hydride. The particular expressed as the fall in cholesterol levels as a percentinert solvent used is not critical but dimethylformamide age of the control level.

is particularly preferred. The temperature is not criti- For such usages, compounds (I) and (la) may be adcal. but the process is preferably carried out at a temministered orally or parenterally as such or admixed perature of from about 0 to C, especially 20 to with conventional pharmaceutical carriers. They may 50C. The reaction can be carried out in one of the be administered orally in such forms as tablets, dispersabove inert atmospheres, and the time may vary widely ible powders, granules, capsules, syrups and elixirs, and and is usually in the range of l to 24 hours. Recovery parenterally as solutions, suspensions, dispersions,

emulsions and the like, e.g., a sterile injectable aqueous suspension. These pharmaceutical preparations may contain up to. about 90 percent of the active ingredient in combination with the carrier or adjuvant.

dicated below which may be prepared by conventional techniques and are useful as a hypocholesterolemic agent at a dose of one tablet or capsule 2 to 4 times a day.

Furthermore, these compounds of formula (I) and (la) may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid and, accordingly, are included within the scope of the invention. Representative of such salts are the mineral acid salts, suchas the hydrochloride, hydrobromide, sulfate, phosphate and the like The following pharmaceutical compositions are formulated with the indicated amount of active agent using ,conventionaltechniques. The injectable suspension and the oral liquid suspension represent formulaq tions useful as unit doses and may be administered as a hypocholesterolemic-agent. The injectable suspension is suitable for administration once or twice a day whereas the oral liquid suspension is suitable administered 2, to 4 times per day for this purpose.

Ingredients l a-hydroxy-p-chlorophenethyl) i Weight (mg) sterile injectable suspension oral liquid suspension -l-(p-chlorophenyl)-2.3-dihydroisoindole 200 200 sodium carboxy methyl cellulose USP 1.25 12.5 methyl cellulose 0.4 v polyvinylpyrrolidone 5 lecithin 3 benzyl alcohol 0.01 magnesium aluminum silicate 47.5 flavor q.s. color q.s.

' methyl paraben, USP 4.5 propyl paraben, USP 1.0 polysorbate 80 (e.gv Tween 80) USP 5 sorbitol solution, 70% USP 2,500 buffer agent to adjust pH for desired stability q.s. q.s. water for injection, q.s. to '5 ml.

q.s. to 1 ml.

and the organic acids salts, such as the succinate, ben- EXAMPLE 1 zoate, acetate, p-toluenesulfonate, benzene-sulfonate, maleate, malate, tartrate, methanesulfonate, cyclohexylsulfamate pyroglutamate and the like.

The cholesterol reducing effective dosage of active ingredient employed in the treatment of lipidemia may vary depending on the particular compound employed and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds (I) and (la) are administered at the daily dosage of from about 0.5 milligrams to about 100 milligrams per kilogram of animal body weight, preferably given in divided doses two to four times daily, or in sustained release form. For most large mammals, the

total daily dosageis from about to about 1,500 milligrams. Dosage forms suitable for internal use comprise from about 7.5 to about 750 milligrams of the,active compounds in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The preferred pharmaceutical compositions fromthe standpoint of preparation and ease of administration are solid compositions, particularly hardfilled capsules and tablets containing from about 200 to 500 milligrams of the active ingredient.

A representative formulation suitable for administra-- tion is a tablet or capsule containing the ingredients inchlorophenyl)-3-ethoxy-lH-isoindole,

isoindole in 500 ml of absolute dimethylformamide is then added dropwise. After completion of the addition,

the mixture is stirred at room temperature for 2 hours and 47.0 g. of p-chlorophenacyl bromide in 500 ml of absolute dimethylformamide is then added dropwise. The mixture is stirred at room temperature overnight. The solvent is evaporated under reduced pressure and theresidue-dissolved in methylene chloride and washed with water to yield l-(p-chlorophenacyl)-l-(pp 99lOl"C).

Following the above procedure but using an equivalent amount of a. phenacyl bromide; b. p-fluorophenacyl bromide; c. p-methoxyphenacyl bromide;

d. o-trifluoromethylphenacyl bromide; ei m-trifluoromethylphenacyl bromide; f. m-fluorophenacyl bromide:

g. o-fluorophenacyl bromide;

h. p-trifluoromethylphenacyl bromide; i. 3,4-dichlorophenyl bromide;

j. p-methylphenacyl bromide;

k. o-chlorophenacyl bromide or I. m-chlorophenacyl bromide in place ofthe p-chlorophenacyl bromide used therein, there is obtained:

a. l-phenacyl-l-(p-chlorophenyl)-3-ethoxy-1H- isoindole:

b. l-(p-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxylH-isoindole;

c. l-( p-methoxyphenacyl l -(p-chlorophenyl )-3- ethoxy-l H-isoindole;

d. l-(o-trifluoromethylphenacyl)-l-(p-chlorophenyl)- 3'ethoxy-lH-isoindole;

e. l-(m-trifluoromethylphenacyl)-l-(p-chlorophenyl)- 3-ethoxylH-isoindole;

f. l-(m-fluorophenacyl)-l-(pchlorophenyl)-3-ethoxy lH-isoindole;

g. l-(o-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxyl H-isoindole;

h. l-(p-trifluoromethylphenacyl)-l(pchlorophenyl)- 3-ethoxyl H-isoindole;

l-(3.4-dichlorophenacyl)-l-(p-chlorphenyl)-3-ethoxylH-isoindole;

j. l-(p-methylphenacyl)-l-(p-chlorophenyl)-3-ethoxylH-isoindole;

k. l-(o-chlorophenacyl)-l-(p-chlorophenyl)-3-ethoxylHisoindole or l. l-(m-chlorophenacyl)-1-(p-chlorophenyl)-l-ethoxylH-isoindole, respectively.

l-( a-hydroxy-p-chlorophenethyl l -(p-chlorophenyl 2,3-dihydroisoindole.

To 22.5 g of l-(p-chlorophenacyl)-l-(pchlorophenyl)-3-ethoxy-lH-isoindole dissolved in 100 ml of anhydrous tetrahydrofuran and cooled with icebath is added dropwise 100 ml ofa commercial solution of 1 molar diborane in tetrahydrofuran. The solution is stirred for two hours at room temperature after which the solvent is evaporated under reduced pressure. Addition of 100 ml of water is followed by extraction with chloroform, to yield l-(a-hydroxy-pchlorophenethyl)-l-(chlorophenyl)-2,3- dihydroisoindole. m.p.l57-l60C.

The l-( a-hydroxy-p-chlorophenethyl l pchlorophenyl)-2.3-dihydroisoindole of this example is an effective hypocholesterolemic agent when administered orally at a dosage of 250 milligrams twice a day.

Following the above procedure. but using an equivalent amount of a. l-phenacyll-(p-chlorphenyl)-3-ethoxy-1l-lisoindole:

b. l-(p-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxyll-l-isoindole;

c. l-( p-methoxyphenacyl l -(p-chlorophenyl)-3- ethoxyl H-isoindole;

d. l(o-trifluoromethylphenacyl)-1-(p-chlorophenyl)- 3-ethoxyl H-isoindole;

e. l-(m-trifluoromethylphenacyl)-l-(p-chlorophenyl)- 3-ethoxyl H-isoindole;

14 f. 1-(m-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxyl H-isoindole; g. l-(o-fluorophenacyl)-l-(pchlorophenyl)-3-ethoxyll-l-isoindole;

in place of the l-(p-chlorophenacyl)-l-(pchlorophenacyl)-3-ethoxy-lH-isoindole used therein there is obtained:

a. l-(a-hydroxyphenethyU- l-(p-chlorophenyl )-2,3-

dihydroisonidole (m.p. 139l40C);

. l-(a-hydroxyp-fluorophenethyl)-l-(pchlorophenyl)-2,3-dihydroisoindole (m.p. 154l55C);

. l-(a-hydroxy-p-methoxyphenethyl)-l-(pchlorophenyl)-2,3-dihydroisoindole (m.p.

l-( a-hydroxy-o-trifluoromethylphenethyl l pchlorophenyl)-2,3-dihydroisoindole;

e. 1-(a-hydroxy-m-trifluoromethylphenethyl l( pchlorophenyl)l2,3-dihydroisoindole;

. l(oz-hydroxy-m-fluorophenethyl l (-pchlorophenyl)-2,3-dihydroisoindole;

. l-( a-hydroxy-o-fluorophenethyl l -(pchlorophenyl)-2,3-dihydroisoindole;

h. l a-hydroxy-p-trifluoromethylphenethyl l -(pchlorophenyl)-2,3-dihydroisoindole;

. 1-( a-hydroxy-3,4-dichlorophenethyl l -(pchlorophenyl)2,3-dihydroisoindole; (m.p. l40-142C);

. l-( a-hydroxy-p-methylphenethyl l pchlorophenyl)-2,3-dihydroisoindole k. l-(01-hydroxy-o-chlorophenethyl 1 pchlorophenyl)-2,3-dihydroisoindole or 1. 1-( a-hydroxy-m-chlorophenethyl l pchlorophenyl)-2,3-dihydroisoindole, respectively.

EXAMPLE 2 When essentially the same procedure as in example I is carried out using an equivalent amount of l-phenyl- 3-ethoxy-1H-isoindole or 1-(3,4-dichlorophenyl)-3- ethoxy-lH-isoindole in place of the l-(pchlorophenyl)-3-ethoxy-lH-isoindole used therein, there is obtained after treatment with sodium hydride and p-chlorophenacyl bromide, l-(p-ehlorophenacyl)- l-phenyl-3-ethoxyl H-isoindole or l-(pchlorophenacyl)-1-(3,4-dichlorophenyl)-3-ethoxy-1H- isoindole respectively; and after treatment of these products with diborane, there is obtained l-(ahydroxy-p-chlorophenethyl)-l-phenyl-2,3- dihydroisoindole or l-(a-hydroxy-p-chlorophenethyl)- l-(3,4-dichlorophenyl)-2,3-dihydroisoindole (m.p. l26C) respectively.

EXAMPLE 3 When the 1-(a-hydroxy-p-chlorophenethyl)-1- phenyl-2,3-dihydroisoindole of example 2 is dissolved in methanol and treated with a methanolic solution of maleic acid. there is obtained l-(oz-hydroxy-pchlorophenethyl)-l-phenyl-2,3-dihydroisoindole maleate (m.p. l5l-l53C).

Following essentially the above procedure, but using in place of the l-(a-hydroxy-p'chlorophenethyl)-lphenyl-Z,3-dihydroisoindole an equivalent amount of a. l-( a-hydroxy-o-trifluoromethylphenethyl l p chlorophenyl )-2,3-dihydroisoindole;

b. l-( oz-hydroxy-m-trifluoromethylphenethyl l pchlorophenyl)-2,3-dihydroisoindole;

chlorophenyl)-2,3-dihydroisoindole maleate (m.p. 162-l64C);

c. l-( oz-hydroxy-m-fluorophenethyl 1 pchlorophenyl)-2,3-dihydroisoindole maleate (m.p. l92l94C);

d. l(a-hydroxy-o-fluorophenethyl l -(pchlorophenyl)-2,3-dihydroisoindole maleate (m.p. l85l86C);

e. 1-( a-hydroxy-p-trifluoromethylphenethyl l -(pchlorophenyl)-2,3-dihyclroisoindole maleate (m.p. l78-180C);

f. l -(a-hydroxy-o-chlorophenethyl)-1 -(pchlorophenyl)-2,3-dihydroisoindole maleate 1-(a-hydroxy-m-chlorophenethyl)-l-(pchlorophenyl)-2,3-dihydroisoindole maleate (l70-l72C), or

h. l-(oz-hydroxy-p-methylphenethyl l pchlorophenyl)-2,3-dihydroisoindole (m.p. 169 1 70C), respectively.

EXAMPLE 4 Step A:

l-(az-hydroxy-p-chlorophenethyl)- l -(p-chlorophenyl 3-ethoxyl H-isoindole To 10.4 g of l-(p-chlorophenacyl)-l-(pchlorophenyl)-3-ethoxy-lH-isoindole in 100 ml of absolute ethanol, 3.0 g of sodium borohydride are added. The mixture is stirred at room temperature over night. The solvent is then evaporated under reduced pressure. following which the residue is dissolved in methylene chloride, washed with water until neutral, and dried over potassium carbonate. The solvent is evaporated leaving 11.5 g of a solid (m.p. l-l23) which is chromatographed on silica gel to yield two racemic isomers: Mixture A and Mixture B:

Mixture A: m.p. l44-l46 (6.3 g) and Mixture B: m.p. l36-138 (l.8 g)

Step B: 5 l-(a-hydroxy-p-chlorophenethyl)-l-(p-chlorophenyl)- 2,3-dihydroisoindole.

In 20 ml of tetrahydrofuran, 2.1 g of l-(a-hydroxy-pchlorophenethyl l -(p-chlor0phenyl )-3-ethoxyl H- isoindole, (Mixture A: m.p. l44l46) is reduced with 6 ml of commercial diborane in tetrahydrofuran solution at room temperature over night. Initial work-up yields the title product; m.p. 159-162C (m.p. of the maleic acid addition salt l91l92C).

When the same reduction is carried out with Mixture B of Step A (m.p. l36l38C), the corresponding product is isolated as the maleic acid addition salt. m.p. l l9-l2lC. This product is inactive.

2O EXAMPLE 5 Step A: 3-(a-hydroxy-p-chlorophenethyl)-3-(p-chlorophenyl)- phthalimidine 2 One gram of 1(a-hydroxy-pchlorophenethyl)-1-(pchlorophenyl)-3-ethoxy-lH-isoindole (Mixture A, Step A of example 4), is heated in ml of 95% ethanol and 1 ml of 2N hydrochloric acid at 55-60C for 90 minutes. After evaporation of the solvent, the residue is filtered and washed with water and recrystallized from methylene chloride/hexane to yield the title racemic isomer A: mp. 21 l2l2.

Step B: 1-( 04-hydroxy-p-chlorophenethyl 1 p-chlorophenyl 2,3-dihydroisoindole.

When the product from Mixture A of Step A of this example is treated with diborane in accordance with the process of Step B of example 4, there is again obtained l-( oz-hydroxy-p-chlorophenethyl l pchlorophenyl)-2,3-dihydroisoindole (m.p. 159-l62C).

EXAMPLE 6 Step A: 3-( pchlorophenacyl )-3-(p-chlorophenyl phthalimidine.

When the acid hydrolysis procedure of Step A of example 5 is carried out using l-(p-chlorophenacyl-l-(pchlorophenyl)-3-ethoxy-lH-isoindole of example 1, there is obtained 3-(p-chlorophenacyl)-3-(pchlorophenyl)-phthalimidine (m.p. l92l94C).

Step B: 3-( a-hydroxy-p-chlorophenethyl )-3-( p-chlorophenyl phthalimidine.

When the product of Step A is treated with sodium borohydride using the process of Step A of Example 4, there is obtained after chromatography 3-(a-hydroxyp-chlorophenethyl)-3-(p-chlorophenyl)-phthalimidine (m.p. 2l l2l2C).

Step C: l-( a-hydroxy-p-chlorophenethyl l p-chlorophenyl 2,3-dihydroisoindole.

When the product of Step B of this example is treated with diborane using the process of Step B of example 4, there is obtained l-(a-hydroxy-p-chlorophenethyl)- l-(p-chlorophenyl)-2.3-dihydroisoindole (m.p. l59l6lC) EXAMPLE 7 l-( a-hydroxy-p-chlorophenethyl l p-chlorophenyl 2.3-dihydroisoindole.

When the product of Step A from example 6 is treated with dibroane using the process of Step B of example 4. there is obtained l-(a-hydroxy-pchlorophenethyl)-l-(p-chlorophenyl) 2,3- dihydroisoindole.

EXAMPLE 8 Step A: l-(p-chlorophenyl)-3-oxo-isoindoline acetic acid.

Into a flask equipped with a mechanical stirrer, condenser and dropping funnel is charged under nitrogen 13 grams of sodium hydride in 250 ml. of anhydrous dimethyl formamide. To this. 136 grams of l-(pchlorophenyl)-3-ethoxy-lH-isoindole in 500 ml of absolute DMF is added dropwise. After completion of the addition, the mixture is stirred at room temperature for 2 hours following which 77.5 grams of methylbromoacetate is added dropwise. After standing at room temperature over night, the solvent is evaporated under reduced pressure and the residue is dissolved in methylene chloride. This solution is washed with water and after separation, the organic phase is dissolved in 850 ml of methanol and warmed on the water bath 2 hours with 750 ml of 2N hydrochloric acid. The solvent is evaporated under reduced pressure and the residue is dissolved in 2N sodium hydroxide. After extracting with ether. a recemic mixture of the and isomers of l-(p-chlorophenyl)-3-oxo-isoindoline-acetic acid is precipitated from the aqueous layer by the addition of 2N hydrochloric acid (m.p. 234-236).

To 222 grams of the racemic mixture prepared as above in 2,500 ml of methanol is added 295.0 grams of brucine in 800 ml. of methanol. From the solution, 260 g. of a solid complex precipitates which is filtered off, suspended in 500 ml. of methanol and acidified with 160 ml of 2N hydrochloric acid. On cooling, the acid crystallizes out, is filtered and then recrystallized from methanol with a melting point of 2162l7 and an optical rotation of a =+253. (The optical rotations in this example are measured at a concentration of lOmg/ml in ethanol at 23C using the sodium D-line).

The solution containing the acid complexed with brucine is evaporated to an oil, which is dissolved in methanol and treated with 2N hydrochloric acid. The solid is filtered off and recrystallized from methanol (mp. 2l52l6; a,,=-244).

Following essentially the above procedure. but using an equivalent amount of l-phenyl-3-ethoxy-1H- isoindole or l-(3.4-dichlorophenyl)-3-ethoxy-lH- isoindole in place of the 1-(p-chlorophenyl)-3-ethoxylH-isoindole used therein, there is obtained the and isomers of l-phenyl-3-oxo-isoindoline-acetic acid or l-(3,4-dichlorophenyl)-3-oxo-isoindolineacetic acid respectively.

Step B: (+)-3-( p-chlorophenacyl )-3-( p-chlorophenyl phthalimidine.

Thirty grams of the acid above is treated with 60 ml. of thionylchloride under nitrogen in 300 ml. of dichloroethane and drops of dimethylformamide. The

mixture is refluxed for 30 minutes at 50 to 60 and the solvent is evaporated under reduced pressure. The crude acid chloride, (+)-l-(pchlorophenyl)-3-oxoisoindoline acetic acid chloride, is dissolved in ml of dichloroethane and to this solution is added 48 gm. of chlorobenzene. The mixture is cooled to 50 and 26 grams of aluminuim chloride is added in small portions. After 2 hours. the mixture is allowed to warm to room temperature. The reactants are then poured on ice, extracted with methylene chloride. washed with sodium carbonate solution, dried and evaporated. The crude material (58 g) is dissolved in methylene chloride and ether is added to form a cloudy mixture. A seed crystal is added to crystallize the (+)-3-(pchlorophenacyl)-3-(p-chlorophenyl)phthalimidine, (mp. l7l-l72; a,,=+332).

The ()-3-(p-chlorophenacyl)-3-(p-chlorophenyl)- phthalimidine (mp. l72; a,,33l) is obtained following the above procedure and chromatographing on silica; but using an equivalent amount of ()-3-(pchlorophenyl)-3-oxo-isoindoline-acetic acid in place of the (+)-l-(p-chlorophenyl)-3-oxo-isoindoline acetic acid to prepare the ()-l-(p-chlorophenyl)-3-oxoisoindoline acetic acid chloride.

Following the above procedure but using an equivalent amount of a. benzene; fluorobenzene;

c. methoxybenzene;

d. trifluoromethylbenzene; e. 3,4-dichlorobenzene or; f. toluene in place of the chlorobenzene used therein, there is obtained the and isomers of a. 3-phenacyl 3(p-chlorophenyl)-phthalimidine;

3-(p-fluorophenacyl)-3-(p-chlorophenyl)- phthalimidine;

. 3-(p-methoxyphenacyl)-3-(p-chlorophenyl)- phthalimidine;

d. 3-(p-trifluoromethylphenacyl)-3-(p-chlorophenyl)- phthalimidine;

e. 3(3,4-dichlorophenacyl)-3-(p-chlorophenyl)- phthalimidine or f. 3-(p-methylphenacyl)-3-(p-chlorophenyl)- phthalimidine respectively.

When the (+)-l-(p-chlorophenyl)-3-oxo-isoindolineacetic acid of this example is replaced by an equivalent amount of the or isomer of l-phenyl-3-0xoisoindoline-acetic acid or l-(3,4-dichlorophenyl)-3- oxo-isoindoline-acetic acid there is obtained the corresponding or isomers of l-phenyl-3-oxo isoindoline-acetic acid chloride or l-(3,4-dichlorophenyl)-3- oxo-isoindoline-acetic acid chloride before treatment with the chlorobenzene and the corresponding or isomer of 3-phenyl-3-(p-chlorophenacyl)- phthalimidine or 3-(3,4-dichloropheriyl)-3-(pchlorophenacyl)-phthalimidine respectively after treatment with chlorobenzene.

Step C: (+)-3-(a-hydroxy-p-chlorophenethyl)-3-(pchlorophenyl)-phthalimidine To 25 g. of (+)-3-(p-chlorophenacyl)-3-(pchlorophenyl)-phthalimidine in 500 ml. of absolute ethanol under nitrogen and cooled in an ice bath, 3.0

g. of sodium borohydride are added. The mixture is stirred at room temperature for 2 hours. The solvent is then evaporated under reduced pressure, following which the residue is dissolved in methylene chloride, washed with water until neutral, and dried over potassium carbonate. The solvent is evaporated leaving 32 g. of crude product which is chromatographed on silica gel first with benzene then with increasingly stronger chloroform in benzene solution to yield the title product (23l-233; a,,=+l82) Continue elution with chloroform yields a second isomer (a,,=+79).

Following the above procedure and using ()-3-(pchlorophenacyl)-3-(p-chlorophenyl)-phthalimidine in place of the (+)isomer, there is obtained ()-3-(ahydroxy-p-chlorophenethyl)-3-(p-chlorophenyl)- phthalimidine (m.p. 23l-233; a,,=-l84).

Again continued elution with chloroform yields a second isomer (a,,=-79).

Step D: l -(a-hydroxy-p-chlorophenethyl l pchlorophenyl )-2,3-dihydroisoindole.

In 100 ml. of dry tetrahydrofuran, 4.5 g. of ()-3-(ahydroxy-p-chlorophenethyl)-3-(p'chlorophenyl)-3- phthalimidine(a,,==l84), is cooled with ice and reduced with 30 ml of 1 molar commercial diborane in tetrahydrofuran solution. The mixture is left at 7C for 2 days following which the solvent is evaporated and the product dissolved in methylene chloride. After washing with potassium carbonate and water and drying over potassium carbonate, chromatographing as above with benzene and chloroform yields the title product (a,,=7l).

The l a-hydroxy-p-chlorophenethyl l pchlorophenyl)-2,3-dihydroisoindole of this example is an effective hypocholesterolemic agent when administered orally at a dosage of 250 milligrams twice a day.

When the same reduction is carried out with the isomer of Step A, the corresponding l -(a-hydroxyp-chlorophenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole (a, -l-65) is obtained.

When the above process is carried out with isomer (z=+79) and isomer (a=79), the products obtained are inactive isomers (a=60) and (0z=+59) respectively which are pharmaceutically inactive.

Following the above procedures, but using an equivalent amount of either the or isomer of a. 3-phenacyl-3-(p-chlorophenyl)-phthalimidine;

b. 3-(p-fluorophenacyl)-3-(p-chlorophenyl)- phthalimidine;

. 3-(p-methoxyphenacyl)-3-(p-chlorophenyl)- phthalimidine;

d. 3-(p-trifluoromethylphenacyl)-3-(p-chlorophenyl)- phthalimidine;

e. 3-(3,4-dichlorophenacyl)-3-(pchlorophenyl)- phthalimidine;

f. 3-(p-methylphenacyl)-3-(p-chlorophenyl)- phthalimidine;

g. 3-phenyl-3-(p-chlorophenacyl) phthalimidine or h. 3-(3,4-dichlorophenyl)-3-(p-chlorophenacyl)- phthalimidine,

in place of the (+)-3-(p-chlorophenacyl)-3-(pchlorophenyl)-phthalimidine used therein there is obtained after carrying out the process of Step C, the corresponding or isomers of respectively, and the corresponding or isomers of a. l-(a-hydroxyphenethyl 1 p-chlorophenyl )-2,3-

dihydroisoindole; 1-( a-hydroxy-p-fluorophenethyl- 1 -(pchlorophenyl)-2,3-dihydroisoindole; 1-( a-hydroxy-p-methoxyphenethyl l pchlorophenyl )-2,3-dihydroisoindole d. l-( oz-hydroxy-p-trifluoromethylphenethyl)- l -(pchlorophenyl )-2,3-dihydroisoindole; e. l-( a-hydroxy-3 ,4-dichlorophenetnyl)-1-(pchlorophenyl )-2,3-dihydroisoindole; f. l-( a-hydroxy-p-methylphenethyl 1 pchlorophenyl)-2,3-dihydroisoindole; g. l-( a-hydroxy-p-chlorophenethyl l -phenyl-2,3-

dihydroisoindole or l-(a-hydroxy-p-chlorophenethyl)-1-(3,4-

dichlorophenyl )-2,3-dihydroisoindole,

respectively after carrying out the process of Step D.

EXAMPLE 9 ()-1-(a-hydroxy-p-chlorophenethyl)-l-(pchlorophenyl )-2,3-dihydroisoindole To a suspension of 48.0 grams (0.125 mol) of racemic 1-(a-hydroxy-p-chlorophenethyl 1 pchlorophenyl)-2,3-dihydroisoindole from example 1 in 700 ml. of methanol there is added 19.] g of D-(+)- pyroglutamic acid (D-(+)-2-pyrrolidone-5-carboxylic acid) of an estimated optical purity of percent. The solution is filtered and the product ()-l-(oz-hydroxyp-chlorophenethyl)-l-(p chlorophenyl) 2,3-

dihydroisoindole-D-(+)-pyroglutamate is precipitated by the addition of ether. The product is filtered off and dried (m.p. l80-l 8 1; a,,=5.24; yield 28.0 g, 87 percent).

The free base is liberated by treating a methanol solution of the above salt with 2N sodium hyroxide and extracting with methylene chloride. The product is isolated as an amorphous foam (a,,=-70.25)

To 5.2 grams of the above free base in 5 ml. of methanol, 2.2 g. of percent'phosphoric acid is added following which ether is added to precipitate the phosphate salt of the title compound (m.p. l07-109; a,,=+27.5; yield 7.0 g).

The filtrate remaining above after the separation of the pyroglutamate of the title product is evaporated to dryness to precipitate l oz-hydroxy-pchlorophenethyl)-1-(p-chlorophenyl)-2,3- dihydroisoindole D-(+)-pyroglutamate. I

When the above salt in methanol is treated with 2N NaOH and extracted with methylene chloride. the free base l a-hydroxy-p-chlorophenethyl l pchlorophenyl)-2.3-dihydroisoindole is obtained as a foam. Treatment with L-()-pyroglutamic acid yields the salt (a,,=+5.24) which on treatment with 2N NaOH again yields the pure (+)-l-(a-hydroxypchlorophenethyl l p-chlorophenyl )-2,3- dihydroisoindole (a,,=+70.25; phosphate a,,=-27.5)

When the above process is carried out using an equivalent amount of a racemic mixture of l-(ahydroxy-3.4-dichlorophenethyU-l-(p-chlorophenyl)- 2,3-dihydroisoindole prepared as in example 1 in place of the racemic mixture of l-(a-hydroxy-pchlorophenethyU-l-(p-chlorophenyl)-2,3- dihydroisoindole there is obtained ()-l-(a-hydroxy- 3.4-dichlorophenyU-l-(p-chlorophenyl)-2,3- dihydroisoindole (a,,=64.96; D'pyroglutamic acid salt m.p. l65-l68C.; u -6.96) and (+)-l-(ahydroxy34-dichlorophenethyl)-l-(pchlorophenyl)- 2.3-dihydroisoindole (a,,=+62.5).

What is claimed is:

l. A compound of the formula:

salt

where R and R each independently represent hydrogen or halo having an atomic weight of l9 to 36 and R and R each independently represents hydrogen,

lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, halo having an atomic weight of 19 to 36 or trifluoromethyl provided that when both R and R are trifluoromethyl, they are not on adjacent carbon atoms; or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 which is l-(a-hydroxyp-chlorophenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

3. The compound of claim 1 which is hydroxyphenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

4. The compound of claim 1 which is l(ahydroxy p-fiuorophenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindolet 5. The compound of claim 1 which is l-(a-hydroxyp-methoxyphenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

6. The compound of claim 1 which is l'(a-hydroxyo-trifluoromethylphenethyl)-l-(p-chlorophenyl)2,3- dihydroisoindole.

7. The compound of claim 1 which is l-(a-hydroxym-trifluoromethylphenethyl l p-chlorophenyl )-2,3- dihydroisoindole.

8. The compound of claim 1 which is l-(a-hydroxym-fluorophenethyl)-l-(p-chlorophenyl)2,3- dihydroisoindole.

9. The compound of claim 1 which is l-(a-hydroxyo-fluorophenethyll-l-(p-chlorophenyl)-2,3- dihydroisoindole.

10. The compound of claim 1 which is l-(a-hydroxyp-trifluoromethylphenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

11. The compound of claim 1 which is l-(a-hydroxy- 3,4-dichlorophenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

12. The compound of claim 1 which is l-(a-hydroxyp-chlorophenethyl l phenyl-Z,3-dihydroisoindole.

13. The compound of claim 1 which is l-(a-hydroxyp-chlorophenethyl)-l-(3,4-dichlorophenyl)-2,3- dihydroisoindole.

14. The compound of claim 1 which is l-(a-hydroxyo-chlorophenethyl l-(p-chlorophenyl )-2,3- dihydroisoindole.

15. The compound of claim 1 which is l-(a-hydroxym-chlorophenethyl l p-chlorophenyl )-2,3- dihydroisoindole.

16. The compound of claim 1 which is l-(a-hydroxyp-methylphenethyl l p-chlorophenyl )-2 ,3- dihydroisoindole.

17. A pharmaceutically active compound of the formula with diborane in an inert solvent where X is CO or CHOH; Z is CO or A is hydrogen or which comprises treating a compound of the formula AB together represent a carbon to nitrogen double bond when Z is l -(!JOC h5 3 and R R R R and the proviso are as set out in claim l. The Process according to Claim 20 in which X is with an alkali metal hydride reducing agent in an inert Z solvent, where Z, R R R R and the proviso are as set out in i claim 20. 25. A compound of formula and AB represents a carbon to nitrogen double bond.

22. A compound of the formula R 1-1 lca N OH R R Z A where CH Z, R R R R and the proviso are as set out in 2 claim 23. 26. A process for preparing a compound of the for- Z A mula R where X, Z, R, R R R and the proviso are as set out in claim 20.

2 23. A compound of the formula 3 R NH h R R CH C which comprises hydrolyzing a compound of the formula N O R where 2 R R R R and the proviso are as set out in claim 24. A process for preparing a compound of the formula v 1 N R 2 CH in an inert solvent under acid conditions at a pH below 3, where ,i H Rh 2 A X, R R R R and the proviso are as set out in claim 22.

27. A compound of the formula which comprises treating a compound of the formula CH X i h NH where X. R,R R R and the proviso are as set out in claim 25, with an alkali metal reducing agent in an inert solvent,

28. A process for preparing the compounds of claim Where 17 which comprises reducing a compound of the for- 1 2- 3 4 and the Proviso are as Set out in Claim mula: 2 28 to obtain a product of the formula:

. I g i g Sell/em Where t I and separating the product into its component isomers.

1,7 4 n e proviso are as se out in c aim A compound of the formula 29. A compound of the formula: R

CH -C R OH O 0 where R R R R and the proviso' are as set out in claim where Rh R), R3, R4 and the proviso are as Set out in claim 32. A process for preparing a compound of the formula 30. A process for preparing a compound of the'formula l R l- 3 --C CH CH A o R NH H h 27 which comprises treating a compound of the formula h -COOB with a halogenating agent to form an intermediate of the formula CH COY and thereafter treating said intermediate with a compound of the formula in an inert solvent in the presence of a Friedel Craft catalyst where Y is halo having an atomic weight of about 35 to 80 where Y, R,, R and the proviso are set out in claim 31.

34. A compound of the formula where R R and the proviso are as set out in claim 31. 35. A process for preparing enantiomers of claim 17, which comprises reducing a compound of the formula:

with diborane in an inert solvent to form ture of the formula:

E f/{ l a racemic mixcH -cH 6 OH 4 where R R R and R are as set out in claim 17, reacting said racemic mixture with D-(+)- pyroglutamic acid, separating the resulting diastereoisomers by crystallization and liberating'the enantiomers from the diastereoisomers by treatment with a base.

Claims (35)

1. A COMPOUND OF THE FORMULA:

2. The compound of claim 1 which is 1-( Alpha -hydroxy-p-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

3. The compound of claim 1 which is 1-( Alpha -hydroxyphenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

4. The compound of claim 1 which is 1-( Alpha -hydroxy-p-fluorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

5. The compound of claim 1 which is 1-( Alpha -hydroxy-p-methoxyphenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

6. The compound of claim 1 which is 1-( Alpha -hydroxy-o-trifluoromethylphenethyl)-1-(p-chlorophenyl)-2,3 -dihydroisoindole.

7. The compound of claim 1 which is 1-( Alpha -hydroxy-m-trifluoromethylphenethyl)-1-(p-chlorophenyl)-2,3 -dihydroisoindole.

8. The compound of claim 1 which is 1-( Alpha -hydroxy-m-fluorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

9. The compound of claim 1 which is 1-( Alpha -hydroxy-o-fluorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

10. The compound of claim 1 which is 1-( Alpha -hydroxy-p-trifluoromethylphenethyl)-1-(p-chlorophenyl)-2,3 -dihydroisoindole.

11. The compound of claim 1 which is 1-( Alpha -hydroxy-3,4-dichlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

12. The compound of claim 1 which is 1-( Alpha -hydroxy-p-chlorophenethyl)-1-phenyl-2,3-dihydroisoindole.

13. The compound of claim 1 which is 1-( Alpha -hydroxy-p-chlorophenethyl)-1-(3,4-dichlorophenyl)-2,3-dihydroisoindole.

14. The compound of claim 1 which is 1-( Alpha -hydroxy-o-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

15. The compound of claim 1 which is 1-( Alpha -hydroxy-m-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

16. The compound of claim 1 which is 1-( Alpha -hydroxy-p-methylphenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

17. A pharmaceutically active compound of the formula

18. The compound of claim 17 which is (+)-1-( Alpha -hydroxy-p-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

19. The compound of claim 17 which is (-)-1-( Alpha -hydroxy-p-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.

20. A process for preparing the compounds of claim 1 which comprises reducing a compound of the formula:

21. The process according to claim 20 in which X is -Co-, Z is

22. A compound of the formula

23. A compound of the formula

24. A process for prepaRing a compound of the formula

25. A compound of formula

26. A process for preparing a compound of the formula

27. A compound of the formula

28. A process for preparing the compounds of claim 17 which comprises reducing a compound of the formula:

29. A compound of the formula:

30. A process for preparing a compound of the formula

31. A compound of the formula

32. A process for preparing a compound of the formula

33. A compound of the formula

34. A compound of the formula

35. A process for preparing enantiomers of claim 17, which comprises reducing a compound of the formula: